The RUNX family in breast cancer: relationships with estrogen signaling

Abstract

The three RUNX family members are lineage specific master regulators, which also have important, context-dependent roles in carcinogenesis as either tumor suppressors or oncogenes. Here we review evidence for such roles in breast cancer (BCa). RUNX1, the predominant RUNX family member in breast epithelial cells, has a tumor suppressor role reflected by many somatic mutations found in primary tumor biopsies. The classical tumor suppressor gene RUNX3 does not consist of such a mutation hot spot, but it too seems to inhibit BCa; it is often inactivated in human BCa tumors and its haploinsufficiency in mice leads to spontaneous BCa development. The tumor suppressor activities of RUNX1 and RUNX3 are mediated in part by antagonism of estrogen signaling, a feature recently attributed to RUNX2 as well. Paradoxically, however RUNX2, a master osteoblast regulator, has been implicated in various aspects of metastasis in general and bone metastasis in particular. Reciprocating the anti-estrogenic tumor suppressor activity of RUNX proteins, inhibition of RUNX2 by estrogens may help explain their context-dependent anti-metastatic roles. Such roles are reserved to non-osseous metastasis, because ERα is associated with increased, not decreased skeletal dissemination of BCa cells. Finally, based on diverse expression patterns in BCa subtypes, the successful use of future RUNX-based therapies will most likely require careful patient selection.

Runx2, a target gene for activating transcription factor-3 in human breast cancer cells

“…Runx2 has been shown to be expressed in metastatic breast cancer cells [19] and it promoted breast cancer cell invasion [18]. Expression of genes such as MMP-9, MMP-13, osteocalcin, and bone sialoprotein is regulated by Runx2 suggesting the role of Runx2 in breast cancer cell migration and invasion [20,21,[36][37][38]. The survival of breast cancer cell during metastasis also required Runx2 [22].…”

Histone Deacetylase Inhibitors Repress Tumoral Expression of the Proinvasive Factor RUNX2

“…Factors that are crucial during embryogenesis are often hijacked during cancer progression, and RUNX2 is not an exception. RUNX2 is increasingly recognized in cancer biology for its oncogenic properties and a large number of articles link the deregulation of RUNX2 expression with progression and metastasization of different types of epithelial tumors (1,(3)(4)(5)(6)(7)(8)(9)(10)(11)(12)(13)(14)(15)(16)(17)(18). Regulation of RUNX2 may occur at multiple levels and through multiple signaling pathways.…”

MicroRNA-induced drug resistance in gastric cancer

“…Guo et al pointed that RUNX3 rendered gastric cancer cells more prone to anticancer drugs through preventing expression of MDR-1(P-gp), MRP-1 (multidrug resistance protein-1) and Bcl-2 [31]. Its reduced expression has been demonstrated in several cancers including colorectal cancer, breast cancer and glioma [32][33][34]. The results of this study showed that miR-106a inhibited RUNX3 expression.…”